Benign prostatic hyperplasia (BPH) and its related symptoms are a common condition that affects nearly half of men over age 50 and 90% of men over 80. Lower urinary tract symptoms (LUTS) caused by BPH can be very troublesome, affect an individual's quality of life significantly, and are costly. However, the mechanisms underlying BPH and its associated LUTS remain unclear. Increasing evidence documents a significant positive trophic effect of neural input on prostate growth and function. Nerves are required for BPH growth and function. This proposal hypothesizes that onabotulinumtoxinA (onaBoNT-A)'s greater effect on the prostate neural microenvironment is responsible for its superior clinical efficacy at reducing LUTS in men with BPH as compared to the alpha-adrenergic antagonist Tamsulosin. This is the first study directly comparing the clinical efficacy of onaBoNT-A 200 U injected into the prostate versus 0.4 mg per day of oral Tamsulosin in males diagnosed with moderate to severe LUTS associated with BPH. Male volunteers at the Michael E. DeBakey Veterans Affairs Medical Center - Houston will be randomized on a 1:1 assignment by the data coordinating center to one of two treatment arms: ARM 1: onaBoNT-A 200 U and placebo oral capsule daily; ARM 2: Placebo injection (saline) and Tamsulosin 0.4 mg capsule daily. The primary endpoint will be the mean reduction in American Urological Association Symptom Score (AUASS) at 3 months following treatment. At baseline and 3 months after treatment, BPH affected transition zone biopsies will be obtained to compare gene expression profiles in epithelial and stromal BPH cells of prostates injected with onaBoNT-A and saline (tamsulosin group), respectively, using laser capture microdissection and subsequent RNA extraction. Secondary studies will also examine the effects of Tamsulosin and onaBoNT-A on human BPH prostate tissue proliferation, apoptosis, innervation, stromal response, and angiogenesis. If the proposed hypothesis proves correct, the significance of prostate denervation with onaBoNT-A will be a decrease in urinary tract symptoms that impact patient's quality of life, and the avoidance of less effective and/or intolerable alpha-adrenergic antagonist side effects. A further impact of this study will be the detection of biological markers of onaBoNT-A and Tamsulosin induced gene expression changes that will help in the search for mechanisms of action for each treatment. Data from this study will allow for the intelligent design of targeted therapies that will overcome refractoriness to the current standard of care.